A 3-week-old female infant is referred to metabolic genetics after newborn screening reveals markedly elevated phenylalanine (1,840 micromol/L) with a low tyrosine level and elevated Phe:Tyr ratio. The parents are first cousins from a consanguineous community. Mutation analysis identifies homozygosity for a severe PAH gene mutation on chromosome 12q23.2 (p.R408W). A four-generation pedigree shows affected individuals in multiple branches, both sexes affected, transmission from unaffected parents, and clustering in consanguineous branches marked by double horizontal lines. The inheritance pattern marked **A** in the diagram is most consistent with this family presentation. Which of the following best describes the genetic mechanism underlying this inheritance pattern?

Question

Accepted Answer

B. Each parent carries one mutant allele and one normal allele; the proband inherited two mutant alleles (one from each parent), resulting in homozygosity for the severe mutation. ## Why option 1 is right

The inheritance pattern marked **A** (autosomal recessive inheritance) is the correct classification for phenylketonuria caused by PAH gene mutations. In autosomal recessive inheritance, both parents are phenotypically normal but obligate carriers (heterozygotes), each carrying one mutant allele and one normal allele. The proband is homozygous for the severe mutation (p.R408W), having inherited one mutant allele from each parent. The consanguinity (first-cousin marriage) increases the probability of two carriers having an affected child by concentrating the same founder allele in the family. The pedigree shows affected individuals in both sexes equally, transmission only from unaffected carrier parents, and clustering in consanguineous branches—all hallmarks of autosomal recessive inheritance as documented in the Vockley et al. guideline.

## Why each distractor is wrong

- **Option 2**: This describes X-linked recessive inheritance, where affected males transmit the carrier state to all daughters but not sons. The pedigree shows affected females and affected males transmitting to offspring (indirectly through carrier daughters), which is inconsistent with X-linked recessive pattern.

- **Option 3**: This describes X-linked dominant inheritance, where affected males transmit the trait to all daughters and no sons. The pedigree shows unaffected parents with affected children, which excludes X-linked dominant inheritance.

- **Option 4**: This describes Y-linked inheritance, where only males are affected and all sons of affected males are affected. The pedigree clearly shows affected females (the proband) and unaffected fathers with affected daughters, which completely excludes Y-linked inheritance.

**High-Yield:** Consanguinity + homozygous mutation + both sexes equally affected + unaffected parents = autosomal recessive inheritance; PAH gene mutations causing classical PKU follow autosomal recessive inheritance on chromosome 12q23.2.

[cite:Vockley J, Andersson HC, Antshel KM, et al. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet Med. 2014;16(2):188-200.]

Answer

A. The proband inherited the mutant allele on the Y chromosome from the father; all sons of affected males are affected

Answer

C. The proband inherited the mutant allele exclusively from the father; all daughters of affected males are carriers

Answer

D. The proband inherited a single mutant allele from the affected mother; males do not transmit the trait to offspring

Explanation

Why option 1 is right

Why each distractor is wrong

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